Abstract Type 2 diabetes (T2D), particularly associated with obesity, is an epidemic in the US and worldwide and it is the leading cause of renal diseases, non-traumatic loss of limb and blindness. Despite the fact that there are current antidiabetic drugs, such as insulin secretagogues and metformin, used in the treatment of T2D, there is an urgent medical need of additional targeted therapies for an improved management of this disease in patients in which these current drugs have moderate efficacy. As T2D progresses, there is exacerbated and uncontrolled hepatic glucose production that strongly contributes to chronic hyperglycemia, a major cause of the various diabetic pathologies. Acetylation of the transcriptional coactivator PGC-1? selectively suppresses hepatic glucose production and ameliorates T2D. We have used a series of chemical high throughput and secondary assays to identify a small molecule, SR-18292, that increases PGC-1? acetylation, suppressing its gluconeogenic activity. SR-18292 inhibits glucagon and PGC-1?-dependent gluconeogenic gene expression through increased binding between PGC-1? and the GCN5 Acetyl Transferase, displacing the transcription factor HNF4? from gluconeogenic promoters and reducing epigenetic histone activation marks. In diabetic mice, SR-18292 decreases hepatic glucose output, hyperglycemia and increases liver insulin sensitivity. Combined, these studies support targeting this pathway for potential therapeutic intervention for T2D. Thus, the primary goal of this application is to characterize SR-18292 and optimize analogs that could have the potential to become a new anti-diabetic drug therapy in T2D. We will perform a complete SAR (structure and activity relationship), DMPK (drug metabolism and pharmacokinetics), toxicity and a series of in vitro and in vivo metabolic studies to validate the pathway and to identify a SR-18292 analog with robust anti-diabetic activities. The experimental design is focused on two aims: 1) SAR and DMPK studies based on the SR-18292 molecule scaffold using in-vitro and in-vivo assays and target identification (Specific Aim 1) and, 2) toxicology and in-vivo metabolic studies using the SR-18292 analog (Specific Aim 2). The outcomes of this proposal will provide significant contribution to the early-stage preclinical validation for the SR-18292 analogs as therapeutic leads for management of T2D and insulin resistance.